There is a fundamental lack of clinically-relevant, objective biomarkers for aiding in the diagnosis of depression and for predicting antidepressant treatment response. Until such biomarkers become available, clinicians will continue to make diagnostic determinations and choose treatments based on heterogeneous and subjective reports of symptoms, instead of neurobiological mechanisms. The long-term goals are to improve the identification of clinical depression and the treatment of mood disorders through the discovery of clinically-relevant biomarkers. Towards this end, the candidate proposes (1) a training objective to acquire expertise in biomarker discovery, with a focus on psychophysiologic methods; (2) a research objective to study underlying mechanisms of ketamine's antidepressant effects via a series of psychophysiological and cognitive biomarker experiments; and (3) a team of supervisory mentors with experience in biomarker discovery, psychophysiology, and clinical neuroscience necessary for her training and research goals. The central hypothesis is that anxiety-potentiated startle and reward responsiveness will be biomarkers for the clinical course and treatment response of mood disorders. We propose to use ketamine as a model of treatment. The rationale for this proposed research is that, while ketamine has a rapid and robust antidepressant effect in many patients with depression, no biomarkers exist to predict response. There is strong preliminary evidence that ketamine's antidepressant effects are especially significant in depressed patients with anxiety; thus, it is possible that anxiety-potentiated startle and reward responsiveness will provide objective biomarkers of anxious depression. We propose three specific aims to develop objective biomarkers: 1) Determine the relationship between biomarkers (startle and reward responsiveness) and subjective anxiety in patients with mood dysregulation; 2) Determine if pre-treatment biomarkers predict response to ketamine; and 3) Determine the effect of ketamine on the biomarkers. Under the first and second aims, we will measure pre-treatment biomarkers (startle and re- ward responsiveness) across a heterogeneously-diagnosed sample of patients experiencing depression, after which predictors to ketamine's antidepressant response will be analyzed. Under the third aim, we will measure post-ketamine biomarkers to understand if the change in biomarkers is related to clinical changes. The approach is innovative because it uses objective biomarkers for subtyping the heterogeneity of depression and predicting ketamine response. The proposed research is significant, because it is has the potential to advance and expand understanding of how objective measures can be used to predict antidepressant treatment response and to subtype depression. Overall, the candidate will use this project and its associated training as a model to develop biomarkers.